Phenthiazine derivatives



Patented July 14, y 1953 2,645,640 PHENTHIAZINE DERIVATIVES PaulCharpentier, Choisy-le-Roi, France, assignor to Societe des UsinesChimiques Rhone- Poulenc, Paris, France, a French body corporate NoDrawing. Application December 17, 1951, Serial No. 262,171. In FranceDecember 21, 1950 wherein It represents a hydrogen, chlorine or bromineatom or a methyl or methoxy group in the 6- or 8-position,

' X represents either a chlorine or a bromine atom in the 1- or3-position,

A represents a divalent, straight or branched aliphatic chain containingfrom 2 to 5 carbon atoms and R1 and R2 represent either individualmethyl or ethyl groups or divalent groups which together with theadjacent nitrogen atom form a mononuclear heterocyclic ring. a

In a preferred form of the invention, A repre-. sents an alkylene groupcontaining from 2 to 5 carbon atoms and R1 and R2 each represent amethyl or ethyl group or together represent the atoms necessary tocomplete a pyrrolidine, piperidine or morpholine nucleus.

The compounds of the present invention are prepared from a meta-chloroor-bromo diphenylamine (which may be substituted by a further chlorine orbromine atom or by a methyl or methoxy group) by known methods for theconversion of a diphenylamine into a N-dialkylaminoalkylphenthiazine. Bythe expression known method is meant any method heretofore described inthe chemical literature- One preferred process for preparing the newcompounds involves condensing a phenthiazine compound represented by thegeneral formula:

(wherein R and X are as hereinbefore defined) with a tertiary aminoalkylhalide of the formula: R1 In wherein Y represents a halogen atom and R1and R2 have the significance hereinbefore defined and A1 represents adivalent straight or branched aliphatic chain containing from 2 to 5carbon atoms which may be the same as the chain represented by A ingeneral Formula I or, in the case of a branched chain, an isomeric formthereof.

The reaction is preferably carried out in the presence ofan acid-bindingagent, being preferably a member of the class consisting of alkalimetals and their derivatives, e. g. hydroxides, hydrides, amides,alcoholates and metal-alkyl or metal-aryl compounds. The preferredacidbinding agents are sodamide, metallic sodium, powdered sodium andpotassium hydroxides, lithium hydride, sodium tertiary butylate, butyllithium and phenyl lithium.

The reaction is also preferably carried out in an organic non-ionicdiluent which is a solvent for at least one of the two reactants at orin the neighbourhood of the boiling point of the solvent. It isparticularly advantageous to use the tertiary aminoalkyl halide in theform of the free base in solution in an organic solvent, for example,benzene, toluene or xylene, and to add the solution to a heated(preferably boiling) mixture of the phenthiazine compound, anacid-binding agent and said organic solvent. The reaction can also becarried out without added acid-binding agent by introducing the solutionof tertiary aminoalkyl halide, a little at a time, into moltenphenthiazine compounds. When following either of these two procedures,it is necessary in order to avoid loss of organic diluent that thereaction vessel be an autoclave or be fitted with a reflux condenser.

The tertiary aminoalkyl halide can be employed in the form of an acidsalt but, in this case, it is obviously necessary to add a greaterproportion of acid-binding agent in order to neutralize the acidliberated from the acid salt.

When the halogen and nitrogen atoms of a dimethylordiethylaminohalogenopropane are substituted on adjacent carbon atoms, asfor example in the case of l-dimethylamino-Z- chloropropane, theexpected product having the following chain:

is not obtained but instead a mixture of this product and its isomerhaving the chain:

\N/ Bi V this specification and in the appended claims amine of thegeneral formula:'- 1

R2 7 :7 I v with a halogeno alkyl phenthialtine drummer:

mula:

. JIM-Y1 I 1 wherein X, R1, R2, A1 and Y are as hereinbefore defined.This method is particularly suitable in the case where A1 has thefromula -'(CH2 )n, it having the value 4 or 5. 5 Y aThehalogenophenthiazine compounds employed as starting material in oneor'othe'r of the above-mentioned processes are prepared by thecycli's'ation' ofr a 5 'meta hal0genodiphenylamine with sulphur,desirably inthepresence ofiodine ascatalyst.

The cyclisatio'n leads to a mixture of isomers which can be separated-by the applicationbf no conventional techniques. "In the case of meta-'f monochloro diphenylamine:

lisation from a suitable solventsuch asbenzene.

When compounds or the type inwhich R is a substituentjn the .Jform.of;=-.a;chlorine or bromine atomaor a methyl or'methoxy group,thestarting material is preferably. a:3-halogenos-3-R-substitutedediphenylamine thecyclisation of whichashereinbeforeindicated leadsto a mixture of isOmers hich-can beseparated as hereinbefore described; .Such separation is notyhowever,es: sential and Where it is not effected',i.:a-mixture of isomericN-aminoalkylphenthiazines is produced. It should be understood thatwhere in reference is made to a halogeno-(or chloroor bromo)-phenthiazine there meant in the absence of a qualifying termaphenthiazine which containsa halogen (or chlorine or'bromine)'subfstituent in the 1=-' org-position or mixture of the respectiveisomers. Similarly by reference to a disubstituted phenthiazine e.' g. adihalogeno- (or dichloroor dibromo-dphehthiazine is meant a phenthiazinein which a first substituent is in l tics, i u tholytics and fungicides.

the 1- or 3-position and the second substituent is in the 6- or8-position or a mixture of the respective isomers.

' The products of this invention possess-valuable Itherapeutieproperties which "renders them useful as antihistaminics,ganglioplegics, spasmolylocal anaesthetics, analgesics, sympa- They alsopossess an appreciable bactericidal eiTect on the tubercle bacillus.Finallmthey have proved to be particuj larly interesting as potentiatorsof general anaes- "assessor analgesics and of local anaesthetics. Bytheterm potentiator we mean a material which increases the duration oleffect of the active substance.

Of outstanding importance are the isomeric N(3'-dimethylamino-propyl)-chlorophenthiazines, the hydrochlorides ofwhich melt at 179-130" C. and l69 l7o C. respectively.

The. following examples illustrate the invention. The melting pointsgiven are the instantaneous melting points on the Maquenne block.

Example I To a boiling suspension of 11.6 g. of chlorophenthiazine(consisting of' a mixture of two isomers melting at 196-193 C. andlie-117 C. respectively, the latter in minor proportion) and 2.4 g. ofsodamide in 60 cc. of xylene, there are added over a period of one hour7.5 g. of 3-dimethylamino-l-chloropropane in solution in its own weightof Xylene. At the end of the addition, heating is continued for one hourunder reflux. After cooling, the contents are taken up in acidifiedwaterrand the xylene separated. The aqueouslayer is made stronglyalkalineby means of sodium hydroxide in order to liloerate the baseandthis is extracted with ether. On distillation of the etherealextract, there is. obtained 10 (3-dimethylaminoepropyl) -chlorophenthiazine which distils at 200to205 (l under a pressure ofO.8"mm.'I-Ig. Its hydrochloride, recrystallised from chlorobenzene,melts at'177 to 178 C. .while' the picrate melts at, 172-173 C.-

F'r'or'n the" recrystallisation liquors .canbe isolated the isomerichydrochloride melting at 169- 7 (3.; the corresponding picrate m'elts'at13'7- 13s c... V V V l 1.; Emqmplell By operating as in Example I butstarting from chlorophenthiazine.(melting at 196 to 198 1 C.) there 'isobtained '10.-(3'-di,-methylamino-.

propyl) -chlorophenthiazine 'which' distils at 200 to. 205 C.:under'fapressure'of 0.8 mm. Hg, of which the hydrochloride melts at177to 178 C. and the picr'ate ati 172 -173? C.' I v I EmampleIII a heated(12 5 0.) suspension of2 8 g. of chlorophenthiazine (melting at 116 to117 C.) and 7.2 g. of finely powdered caustic'soda (98%) in 159 cc.otxyl'ene, there is added littleby little over a period of half anjhour64'ccs1'of a xylene solution' 'conta'ining .18 g. or" 1-dimethylam ino-3 chloropro'p'ane. At theend of the addition, heating is continued underreflux for a further period of one anda half hours. Following theprocedure of Example I there"is obtained 19.6 g. of 10 (3 dimethylaminopropyl) -ehlorophenthiazine whi-chboils-at 203 to 23 C. under apressure. of 0.7 mm. ligand of whichthe hydrochloridegonrecrystallisation from absolute alcohol, melts at 169 to 170 C.

Example IV By operating as in Example I but starting from sists ofamixture of l-(2-dimethylamino-1 propyl) -chlorophenthiazine and(1-dimethylamino-2-propyl) -chlorophenthiazine with a predominance ofthe first mentioned isomer, the hydrochloride of which, recrystallisedfrom absolute alcohol, melts at 236 to 237 C.

Ear-ample V To a boiling suspension of 11.6 g. of chlorophenthiazine and2.4 g. of 80% sodamide in 60 cc. of xylene there are added over a periodof one hour 6 g. of 1-dimethylamino-2-chloroethane in solution in itsown weight of xylene. At the end of the addition, heating is continuedfor one hour under reflux. After cooling, the mixture is taken up inacidified water and the xylene separated. The aqueous layer is renderedalkaline by means of sodium hydroxide in order to liberate the base andthis is extracted with ether. On distillation of the etheral extract,there is obtained 10- (2- dimethylaminoethyl)-chlorophenthiazine whichdistils at about 195 C. under a pressure of 0.9 mm. Hg.

Its hydrochloride, which is very slightly soluble in cold water, meltsat 220 to 221 C. when recrystallised from alcohol.

Example VI By operating as in Example V but starting froml-diethylamino-Z-ch1oroethane there is obtained 10 (2diethylaminoethyl)-ch1orophenthiazine which distils at 215 C. at apressure of 2 mm. Hg and the hydrochloride of which, recrystallised fromchlorobenzene, melts at 165 to 166 C.

Example VII By operating as in Example V, but starting from1-diethylamino-Z-chloropropane there is obtained a crude base distillingat 230 to 235 C. under a pressure of 3 mm. Hg and which is composed of amixture of 10-(2'-diethylamino-1'- propyl) -chlorophenthiazine and of10-(1-diethylamino 2'- propyl) -chlorophenthiazine with a preponderanceof the first mentioned isomer; the hydrochloride of this lattercompound, recrystallised from chlorobenzene, melts at 200 to 201 C. andis very slightly soluble in cold water.

Example VIII By operating as in Example V but starting from3-dimethylamino-2.2-dimethyl 1 chloropropane there is obtained 10 3'-dimethylamino 2.2 dimethylpropyl) chlorophenthiazine which distils at220 C. under a pressure of 3 mm. Hg and the hydrochloride of whichrecrystallised from chlorobenzene, melt at 182 to 183 C.

Example IX "To a boiling suspension of 13.9 cc. of bromophenthiazine and2.5 g. of sodamide (80%) in 80 cc. of Xylene there are added over aperiod of one hour 8 g. of 3-dimethylamino-l-chloropropane in solutionin its own weight of xylene. At the end of the addition, heating iscontinued for one hour under reflux. After cooling, the mixture is takenup in acidified water and the xylene separated. The aqueous layer ismade alkaline by means of sodium hydroxide in order to liberate the baseand this is extracted with ether. On distillation of the etherealextract there is obtained '10- (3-*dimethylaminopropyl)bromophenthiazine which distilsat 186 C. under a. pressure of 0.08 mm.Hg. Its hydrochloride melts at to 171 C. I v

Example X By operating as in' Example IX but starting from1-dimethylamino-2-chloropropane instead of3-dimethylamino-l-chloropropane there is obtained, after distillation ofthe ethereal extract,

.a crude base which distils at to 192 C. under a pressure of 0.15 mm.and is composed of a mixture of 10 -(2- dimethylamino 1'- propyl)bromophenthiazine and of 10- (1'-dimethylamino 2-propyl)-bromophenthiazine with a predominance of the first mentioned isomer,the hydrochloride of which, recrystallised from butyl alcohol, melts at203204 0.

Example XI By operating a in Example I, but starting with 7.7 g.3-dimethylamino-3-methyl-l-chlorobutane and 10 g. of chlorophenthiazinethere is obtained 10 -(3'- dimethylamino 3- methyl 1- butyl)chlorophenthiazine, B. P.= to 205 C. under a pressure of 0.1 mm. Hgwhich, after recrystallisation from ether, melts at 123 C.

Eaiample XII By operating as in Example I, but starting with 8.8 g. ofZ-dimethylamino-1-chlorobutane and 10 g. of chloro-phenthiazine there isobtained 10 (2- dimethylamino-1'-butyl) chlorophenthiazine, B. P.=171 to187 C. under a pressure of 0.11 mm. Hg, the hydrochloride of which meltsat 209 to 210 C.

Example XIII In the same manner, starting with 14.2 g. ofS-dimethylamino-l-chlorobutane and 20.4 g. of chlorophenthiazine thereis obtained 10-(3'- dimethylamino 1'- butyl)- chlorophenthiazine,

B. P.==203 to 204 C. under a pressure of 0.2 mm.

Hg, the hydrochloride of which melts at 184 to 185 C.

Example XIV Emample XV Starting from 9.6 g. of 3-dimethylamino-1-chloropentane and 15 g. of chlorophenthiazine there is obtained10-(3-dimethylamino-l'-pentyD-chlorophenthiazine, B. P.=203 to 206 C.under a pressure of .15 mm. Hg, the acid oxalate of which melts at 131to 133 C.

Example XVI By operating as in Example V, but starting fromfi-chloroethyl-N-pyrrolidine there is obtained 10-(2'-pyrrolidine-ethyl) -chlorophenthiazine distilling at 230 C. at apressure of 1.5 mm. Hg and the hydrochloride of which, recrystallisedfrom chlorobenzene, melts at 164 C.

Example XVII To a suspension held at 125 C. of 11.6 g. ofchlorophenthiazine and 3 g. of finely powdered 98% caustic soda in 60cc. of xylene there are added over a period of one hour 7.5 g. of N-(B-chloroethyD-piperidine in solution in two parts of xylene. The processis then continued as in Example III. i There is obtained 10 (2'.-'.-pieri"- 'dinoeth-yl) -chlorophenthiazine which distils at 245 C. under apressure of 2.5 mm. Hgandthe hydrochloride of which, recrystallised fromchlorobenzene, melts at 187 to 188 C.

. p v 7' Example XVIII l By operating. as in Example V, but startingwith ,8-chloroethyl-N-morpholine there is obtained 10 (2'morpholino-ethyl)Pchlorophenthiazine which distils at 260 C. under apressure oi 2 mm. Hg and the hydrochloride 'of which,

after recrystallisation from alcohol, melts at 192 to l9'3"-"C. rExample XIX Starting rrom 11.7 g. of 3"-pyrrolidino-l-chloropropane and15 g. of chlorophenthiazinethere is obtained l (2.-pyrrolidino-1-propyl)chloro'- phenthiazine, l3. P.c.i=210 C.

e 'ErampZe X Starting from L2 g. of 3-dimethylamino-lchloropropane and7.4 g. of methylchlorophenthiazine (M. P; 267 to 270 C. prepared byconassesses of s" phur 3methyl-3-chlorodiphenylamine in the presence ofa little iodine at 160 to 180 C.) there is obtained -(3--dimethylamino 1propyl) methylchlorophenthiazine, B. P.o.1,=2e0 to 250 .C., the acidoxalate "er hieh'melts at 120 C. with decomposition.

' Example XXI ssr jor dichlorophenthiazine. (yr. P. 259 to 260 CI;prepared by condensation of sulphur and 3:3-dichlorodiphenylamine inthepresence of a little iodine at 180 C.) in 100 cos. of xylene areheated at 130 Cfuntil dissolution is complete.

There is then rapidly added 0.3 g. of powdered lithium hydri'dathencc.'0f a xylene solution of dimethylamino l chloropropane. Heating iscontinuedunder' reflux for four hours. Aiter'cooling; the mixture istaken up .in 280 cc. of watersand-acidified with hydrochloric acid up tochange of colour of Methyl Orange. The oily layer which separatesisdecanted. It crystallises rapidly, is filtered oii, washed first withwater and then'flwit'h ether and dried undervacuurn in the presence ofsulphuric acid. There'ar'e thus" obtained 4.9 g. of the hydrochloride oil0-(3'- dimethylamino 1 propyl) -dichlorophenthiazine which, afterrecrystallisation from absolute alcohol, melts at2l5 to 218 C.

Example XXII By preceding as in Example XXI, but with 10 cc. of a 37%xylenescltuion of 3-pyrrolidino-lchloropropane ther is obtained thehydrochloride of 10- 3 -pyrrolidino-1 -propyl)-dichlorophenthiazineinthe form at an oil which is takenv up' in waterand rendered alkaline with sodium hydroxide. The baseliberated isextracted with ether and the ether drivenoff; There is obtained aremixedat 05C.

.4185 g. of base which distils at 240 CL'under a pressure of 0.15 mm.Hg. the action of hydrogen chloride in ether on an ethereal solution ofthe base, the hydrochloride is obtained which is filtered off, washedwith anhydrous ether and dried in vacuo over sulphuric acid, M. P.=157to Emarnple XXIV Proceeding as in Example XXI but starting from 5.3 g.of chloroinethoxyphenthiazine (M. P. 201 to 202 (3.; prepared bycondensation of sulphur and 3-chloro-3-methoxydiphenylamine in thepresence or a little iodine at 140 C.), 65 cc. of xylene, 0.3 g. ofpowdered lithium hydride and 10 cc. of xylene solution containing 3.69g. of 3-pyrrolidino-l-chloropropane. After cooling, the mixture is takenup in 200 cc. of water and acidified with concentrated hydrochloric acidin the presence of Methyl Orange. The aqueous layer is decantedandwashed withether. It is rendered alkaline to phenolphthalein withconcentrated sodium hydroxide solution and the base which separates isextracted with ether. The ethereal solution is dried over sodiumsulphate, the ether driven 'oii and'the residue distilled. There isobtain d 3.6 or 10-(3-pyrrolidino-l'- propyl)-chloromethoxyphenthiazinewhich distils at 208 to 210 C. under pressure of 0.1 mm. Hg. Itsoxalate, recrystallised from 50% aqueous alcohol, melts at 172 to 173 C.

Example XXV 15 g. of 10-(5chloro-1,pentyl)-chlorophen thiazine and 20 g.of anhydrous dimethylamine in an autoclave which is hermetically sealed,agitated to dissolve the contents and then left for a week at 20 C. Itis then cooled in ice to enable thecontainer to be opened and the excessof dimethylarnine then driven off. The contents are taken up in 200 cc.of distilled water, acidified to Congo Red with 9 cc. of hydrochloricacid (S. G.=1.1), thenextracted at C. with 150 cc. of toluene. Theaqueous layer is decanted and renderedalkaline with 11 cc. of sodiumcarbonate (S. G.=l.33) and then extracted with cc. of chloroform. Bydistillation of the chloroform extract thereare obtained 9.1 g. of10-(5'-dimethylaminol-pentyl)-chlorophenthiazine, B. P.o.3 =2l5 to 218'C. The oxalate of this base melts at 173 to 174 C. The10-(5-chloro1-pentyl)-chlorophenthiazine (B. P.o.1s=255' C.) employingas starting material is obtained by the action of aluminum chloride incarbon bisulphide on 10(5'phenox l'-pentyl) -chlorophenthiazine (B.P.1=255 to 280 C. which is itself prepared by the action of lphenoxy-iibromopentane (Braun and Steindorii B. 38, 963 (1905)) onchlorophenthiazine in boiling Xylene in the presence of sodamide.

- E am le XXVI 25 g. of 10-(4chloro-l-butyl)-chlorophenthiazine and 17.4g. of anhydrous dimethylamin are mixed at 0 C. in an autoclave which ishermetically sealed, agitated in order to dissolve the'contents and thenleft for 24 hours at 20 C. and subsequently-for 24 hours at 35 C. t isco'oled'in ice in order to permit opening of the container and' theexcess 'dimethylamine then driven off. The contents are taken up in 200cc. of water, rendered acid to Methyl Orange with hydrochloricacid (S.(1:119),v extracted with twosuccessive portions of 100 cc. of tolueneand then with 100 cc; of ether. The aqueous layer is made alkaline with10 cc. ofsodium carbonate (S. G. 1.33) and then extracted with 200 cc.of ether. On distillation there are obtained 17.1 g. of (4'-dimethylamino- 1 -butyl) -chlorophenthiazine, (B. P.0.1s=210 to 2140.). The hydrochloride of this base melts at 161 to 162 C.

The 10- (4-chlor0-1-butyl) chlorophenthiazine employed as startingmaterial is obtained by the action of thionyl chloride in benzene on10-(4'hydroxy 1' butyD-chlorophenthiazine which is itself prepared byhydrochloric acid hydrolysis in 70% alcohol of10-(4-(2"-tetrahydropyranyloxy) 1 butyl) -ch1orophenthiazine (B.P.o.3=230 to 248 C. In order to prepare the latter product dihydropyranis condensed with 4-chlorobutanol in the presence of a few drops ofhydrochloric acid and the 2'-tetrahydropyranyll-chlorobutyl ether (B.P.2=90 to 93 C.) formed is reacted with chlorophenthiazine in boilingXylene in the presence of sodamide.

Example XXVII 31 g. of crude 10-(3'-chloro-1'-propyl)-chl0-rophenthiazine is mixed with 50 cc. of a 30% alcoholic solution ofdimethylamine and the mixture heated in a sealed tube for seven hours at120 C. The alcohol and the excess of dimethylamine are then driven off,the mixture taken up in acidified water and filtered. It is madealkaline with soda and extracted with ether. The ether is driven off andthe residue distilled; there is obtained 10-(3'-dimethylamino-1'-pr0-pyl) -chlorophenthiazine, B. P.0.a=200 to 210 0., the hydrochloride ofwhich melts at 177 to 178" C., the red-coloured picrate at 169 C. andthe methyl sulphomethylate at 140 to 141 C. The 10 (3'-chloro-1'-propyl)-chlorophenthiazine is prepared in a manner analogous to that describedby Gilman and Shirley J. A. C. S. 66, 890 (1944), by the action of'y-chloro-propyl-ptoluene sulphonate on lithium chlorophenthiazine.

I claim:

1. A member of the class consisting of phen- 10 thiazine derivativeshaving the basic structural formula:

01 O f) N CH3 3. A phenthiazine compound having the basic structuralformula:

N 0 CH3 C Hz-C Hr-C Hz-N PAUL CHARPENTIER.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,512,520 Cusic June 20, 1950 2,534,237 Cusic Dec. 19, 1950

1. A MEMBER OF THE CLASS CONSISTING OF PHENTHIAZINE DERIVATIVES HAVINGTHE BASIC STRUCTURAL FORMULA: